Ginsan, a botanic polysaccharide extracted from Panax ginseng, has recently been reported to modulate mucosal immune response. In this study, we investigated the protective effect of Ginsan against fatal Vibrio vulnificus mucosal infection. A lethal dose of V. vulnificus (1.0 × 106 CFU/mouse) was nasally inoculated to mice. The bacterial count in the nasal associated lymphoid tissue (NALT) of the mouse was significantly reduced in the Ginsan-treated group. The Ginsan-treated group showed improved survival compared to the control group (100% vs 18%). To elucidate the effect of Ginsan on modulating host immune response, cytokine mRNA expressions involved in mediating inflammation were determined by semiquantitative RT-PCR in the NALTs of the infected mice. Most of the cytokine mRNAs were similarly expressed as the control group. However, COX-1 mRNA expression level was higher in Ginsan-treated group compared to the control group. The protective effect of Ginsan was antagonized by treating with a specific COX-1 inhibitor, SC-560. Thus, these data suggest that the protective effect of Ginsan against V. vulnificus infection is partly mediated by modulating COX-1 expression.